In vivo intramuscular delivery of plasmid DNA encoding erythropoietin (EPO) using lchor's innovative and proprietary TriGrid electroporation system has resulted in robust constitutive expression of EPO in rodents, rabbits and primates. While high EPO levels are beneficial for patients with blunted responses to EPO, such high expression is not appropriate for chronic renal failure patients who are sensitive to rapid increases in EPO. Development of a physiologically modulated EPO gene therapy with a more direct communication between a patient's anemia and the intramuscularly delivered EPO transgene would thus be of benefit for this latter patient population. The necessities of monitoring hematocrit and titrating doses of the protein would be eliminated. Toxicities could potentially be decreased. Finally, abuse by non-patients would be unlikely. Ichor has demonstrated the feasibility of utilizing anemia-related hypoxia to modulate gene expression from hypoxia-responsive plasmids transfected into anemic mouse muscle. However, this approach must be more thoroughly investigated in a more clinically relevant animal model. Experiments will be performed using rats and will include in vivo screening of HRE-containing plasmids in anemic animals, evaluation of the effect of hypoxia induced by exercise on gene expression, and assessment of hypoxia-modulated EPO transgene expression in a disease model.